Rivaroxaban for acute deep venous thrombosis

When we have a standard therapy for a disease, in this case vitamin
K antagonists (VKA) for deep venous thrombosis (DVT), and a
new therapy comes out, what do we want to know about the new drug?
Is it at least as effective as the old therapy? Because if it’s
not, that ends the conversation. If it’s at least as effective,
that opens the door to further discussion. We also want know if the
new therapy is safe, or at least no more dangerous that what we’re
already using. Then we want to know the cost, because new therapies
aren’t cheap. Bringing a drug to market costs a lot of money and
who gets to cover that cost? The people buying the
medication: patients, insurance companies, the
government.

Let's take a look at rivaroxaban for treatment of DVT and see if
it's something we should add to our treatment quiver or a case of
'the enemy of good is better'.

Part one. The evidence

Who was studied?

The main study looking at rivaroxaban treatment for DVT
study was by the EINSTEIN group published in NEJM 2010. There was a
follow-up study using the same drug for PE but for now, we’ll stick
to DVT. About 3500 patients with acute symptomatic DVT were split
into two groups. Group one got standard therapy with LMWH and an
oral vitamin K antagonist. Group two got rivaroxaban 15 mg/kg bid
for three weeks and then 20 mg per day for the duration of therapy-
3, 6 or 12 months. One thing I don’t like about this study is that
it was funded Bayer (the company that makes the drug) but that’s
the reality with almost all large drug trials. An upside of the
trial is that there was a good representation of the different
causes of DVT- unprovoked, surgery, trauma, immobilization,
estrogen, cancer, previous VTE.

Efficacy and safety

The primary efficacy outcome was recurrent venous thromboembolism.
Both groups were statistically the same: 2.1% for rivaroxaban
and 3% for standard therapy. The primary safety outcome, major
bleeding or what was dubbed ‘clinically relevant non-major
bleeding’, was the same for both groups : 8.1%.

Major bleed rates were around 1% for both groups, and that held up
in the follow-up study looking at rivaroxaban for PE. But
what is a major bleed? It may mean something different to you than
your colleagues. In these trials, a major bleed was defined as:
clinically overt with at least a 2g/dL hemoglobin drop,
bleeding that led to at least a 2 units blood transfusion,
intracranial or retroperitoneal or critical site bleed, or bleeding
that contributed to death.

BMJ Meta-analysis

A meta-analysis in BMJ 2012 looked at the available data on new
anticoagulants (for multiple indications, not just DVT) and found
similar results as the NEJM study, but came to the conclusion that
rivaroxaban was associated with a reduced risk of bleeding. Click
here for an in-depth analysis by Professor Simon Carley.

The BMJ meta-analysis showed that rivaroxaban had
non-inferior efficacy and decreased bleeding rates compared to
VKAs. I don't agree with the argument that this drug has
superiority because of fewer bleeding compications. The rate of
serious bleeding was 1% for both rivaroxaban and VKAs. If you put
lipstick on a pig, it’s still a pig. Bleeding happens and the
new stuff is just as bleedy or just as not bleedy, which ever way
you want to slice it.

A footnote to all of this data is that in the two main NEJM
rivaroxaban studies on VTE and PE, INR was therapeutic about 50-60%
of the time. If INR was therapeutic 100% of the time, would
rivaroxaban have looked so good? We’ll probably never know because
that’s the problem with warfarin and one of the selling points of
this new drug: VKA metabolism is erratic. A 2011 Swedish study
found INR in therapeutic range 76% in 18,000 patients on VKAs. How
would rivaroxaban have fared against this cohort?

Should warfarin be voted out of office?

If the new therapy is no better and no worse than the old therapy
as far as recurrent VTE and bleeding, why would we vote the
incumbent out of office? If this were politics, how would you
campaign against each candidate? Warfarin has a long track record
and we can bring out a lot of its dirty laundry.

Compared to the other drugs your patients are taking, warfarin is a
great drug and a horrible drug. It’s great because it thins the
blood and it’s horrible because it makes patients bleed, has
variable and erratic metabolism, needs frequent monitoring and
patients have dietary restrictions. In the 2010 EINSTEIN NEJM
study, INR was therapeutic (2.0-3.0) just over half the time and
low about a quarter of the time (and this was in a clinical trial
where you would expect tight control). Let’s face it, warfarin is a
fussy drug and your patient will need to give themselves LMWH
shots until goal INR is reached. Self administration of LMWH
can be a barrier to treatment. It’s expensive and, if treatment
becomes prolonged, REALLY expensive.

The new stuff, rivaroxaban, is no worse than the old stuff as far
as efficacy and bleeding. So how is it better? It’s orally dosed so
no shots are needed. It has more reliable metabolism, less drug
interaction, no dietary restrictions, no monitoring. But like any
new drug, you know it’s not going to be cheap and then there’s the
problem of reversibility - the Achilles heel of the new
anticoagulants. Let’s take a look at these two issues. First,
cost.

Part two. Cost

My local pharmacy prices for LMWH, warfarin and rivaroxaban...

LMWH + warfarin for 3 months

LMWH: 70 dollars a dose. Five days at two doses a day: $700.

Warfarin for 95 days: about 10 dollars

INR testing: $44 dollars per test. There are a few INR checks in
the first week and the total number of tests is going to vary but
let’s say 8 total tests that’s one every other week once
therapeutic and some extra in the beginning before therapeutic. Say
$350 for all the INR testing in a three-month period.

Total cash payout $1060

That’s only the money, not the other pains challenges that come
with the warfarin package: diet, requirement of frequent testing,
variable metabolism. It’s no secret that warfarin is metabolized
differently by different people (and even in the same person
depending on the circumstances)

Rivaroxaban for 3 months

First 3 weeks, or 21 days at 15 mg bid is $450

69 days of 20 mg per day, at 11 bucks a pill: $759.

Total cash payout $1209

Part 3. Reversal

The the elephant in the room, and not such a quiet elephant, is
bleeding. No matter how great the drug, if it causes a life
threatening complication we can’t reverse, like severe bleeding, is
it really worth it? In many cases no. That’s still the problem with
dabigatran and why most ED docs, especially those who have cared
for patients with dabigatran bleeds, are not fans.

What do we know about rivaroxaban reversal?

There are a few studies that give some idea on reversal, but
there’s not a mountain of evidence where we can say, “Yup, we’ve
got this covered.”

Rivaroxaban pharmacology basics

Half life 5-9 hours.

Can it be dialyzed? No, it’s 95% protein bound.

Reversal

Is there a product that can reverse rivaroxaban’s anticoagulant
effect? What about PCC? Yes. Kind of. Probably. Maybe.

The study that’s most quoted about reversing rivaroxaban was
published in Circulation 2011. Twelve healthy males were given
rivaroxaban for three days. Rivaroxaban prolonged the PT and
another test called endogenous thrombin potential. OK, blood is
thinner. So we’re following these two lab tests then given
Cofact - a four factor PCC. This has factors II, VII, IX and X,
protein C and S, and antithrombin. As an aside, four factor PCC was
just FDA approved in the United states. Back to the study. So here
are our healthy male subjects, a wad of cash in their pockets, and
the’ve been taking rivaroxaban for three days. Blood is thin,
clotting tests are abnormal and in goes the PCC. What
happened?

PCC immediately normalized the prothrombin time. The control
reversal agent was saline which, not surprisingly, did nor correct
the PT. We know that when PCC works for warfarin, it works
right away. In healthy subjects taking rivaroxaban, it did
just that. The PT was normal right away. The endogenous thrombin
potential was also normalized by PCC, but not by saline. Lab tests
corrected. Good so far. But what about actual bleeding? No
human studies on this, but there is some animal data.

Reversal of rivaroxaban associated bleeding

2012 Anesthesiology- Rabbits given rivaroxaban and then PCC had
improved lab tests but their ears bled just as long. Possibly
under-dosing of PCC in this trial, but, no difference between the
two groups.

2009 Journal of Thrombosis and Hemostasis looked at mesenteric
bleeding in rats given rivaroxaban followed by PCC. PCC at a dose
of 50 units per kilogram almost completely normalized bleeding
time, whereas 25 units per kilogram did not. Going back to the
healthy human volunteer study, 50 units/kg of PCC was the effective
dose used. At 25 units/kg, PCC had no effect.

So there is some animal data that says that PCC has little effect
on bleeding, and other evidence that says PCC reverses bleeding.
But a rat’s gut is not a human’s brain. Can we infer that the
correction of bleeding in this surrogate model applies to the
catastrophic brain bleed you are seeing in resuscitation bay one?
Maybe, but it’s still unknown. The evidence is better for
rivaroxaban than for dabigitran. In the previously mentioned study
on healthy subjects given rivaroxaban, subjects were also given
dabigatran at another time and PCC had no effect on the clotting
tests. There is, however, some animal evidence that PCC may help
with dabigitran associated bleeding.

What about our old friend FEIBA, factor eight inhibitor bypassing
activity? Not everyone has PCC, but a lot of shops have FEIBA.
There is some lab and animal data in baboons and rats given
rivaroxaban that FEIBA reduces prothrombin time and bleeding
time.

On the horizon: recombinant and plasma derived factor Xa antidote,
monoclonal antibodies Still in testing, we’ll let you know more
when and if they’re ready for prime time.

Dosing

Rivaroxaban starts with a loading dose: 15 mg twice daily for
three weeks followed by 20mg once daily. Starting with twice daily
dosing gives better thrombus regression than staring once
daily.

We have another 10a antagonist that we’ve been using for a long
time: low molecular weight heparin. LMWH is dosed by weight
yet rivaroxaban is not. Rivaroxaban is mostly protein bound, giving
it a low volume of distribution. This means that most of the drug
going to moving about in the vascular bed, not body tissue.
In a pharmacokinetics study of forty eight patients with a mix of
males and females, light (<50kg), average (70-80 kg), and
heavy (120kg) subjects were given rivaroxaban. Anticoagulant effect
was similar between genders. In the different body weights,
there was a little more anticoagulant effect in the light group and
a little less in the heavy group, but not enough of a difference
for dose adjustment.

Should you use this drug?

So what to do? We have two therapeutic pathways for DVT. I think
you can be honest with your patients and, if they are candidates
for both, give them the option.

Efficacy, about the same.

Complication rate, about the same. This is always an interesting
part of the conversation. “You have a condition that can
potentially kill you, a blood clot. The treatment for this is to
make your blood thinner. Good thing there, because that’s going to
help you in the long run. The down side to this treatment is that
thin blood means you’ll bleed easier. Eight percent is a fair
number to give, or you can say 1% serious bleeding. There you have
a number needed to harm. How does that compare to number needed to
treat? It’s going to be the same with rivaroxaban and warfarin,
because the efficacy for recurrent VTE is the same.

About the Podcast

Get down-to-earth clinical topics and learn what it really means to work in the ED with the legendary Dr. Rob Orman.
Manageable monthly episodes cover everything you need to know about what's current in EM, plus practice-changing information from Essentials of Emergency Medicine.
This iTunes segment is just one monthly free segment of the full ERcast show. Get over 2 hours of fresh podcast episodes per month and 27 AMA PRA Category 1 credit(s)™ of click-to-claim CME per year when you sign up for the full podcast at hippoed.com/ercast
Don’t forget to download the ERcast app for even more streamlined listening: https://itunes.apple.com/us/app/ercast/id1361125652?mt=8
Like what you hear? Get more great medical education like board review, adaptive Qbanks and self-assessments at hippoed.com/em